PROJECT SUMMARY With advances in technology, the use of extracorporeal membrane oxygenation (ECMO) for severe refractory heart and lung failure has quadrupled in children and increased tenfold in adults in the last 15 years. ECMO is life-saving, but costly, resource-intensive, and high-risk. Up to 30% of pediatric ECMO patients develop neurologic injury. Mortality increases by 89% if injury occurs, and 10%-60% of survivors have clinically important neurologic disability that impairs normal development and school performance. We currently lack the ability to accurately stratify children at risk for death or disability, and to diagnose injury in subclinical phase, thus missing the window for potential neuroprotective interventions. The overall goal of this research is to develop and refine a brain injury multimarker panel for accurate neurologic monitoring at the bedside and early classification of mortality and disability outcomes that will allow real-time neuroprotective interventions, with the ultimate goal to improve neurodevelopmental outcomes of these critically ill children. We hypothesize that circulating markers of brain injury and inflammation can assist in diagnosing difficult-to-image neurologic injury; provide real-time feedback to neuroprotective or potentially deleterious interventions in the intensive care unit; identify patients at risk for long-term neurologic disability; and serve as entry criteria and benchmarks of therapeutic efficacy in future interventional clinical trials through a more refined approach than is currently possible. Based on preliminary data from single and two-center studies, we propose a multicenter prospective observational study (9 centers, 225 subjects) that will seek to determine the association between plasma and imaging markers of brain injury and inflammation during ECMO and short and long-term survival and neurologic outcomes of critically-ill children who require extracorporeal support. Using targeted and discovery approaches, we will address our overall goal in the following specific aims, with the support and well-established research infrastructure of the Johns Hopkins Bloomberg School of Public Health, Pediatric Neurocritical Care Research Group and the Kennedy Krieger Institute: (1) Determine if circulating levels of brain injury markers during ECMO and brain MRI abnormalities at 2 weeks after ECMO are associated with survival at 18 months after ECMO with a score ?85 on the Vineland Adaptive Behavior Scales, third edition (VABS-III); (2) Determine whether the presence and degree of inflammation during ECMO and markers of neuroinflammation on brain MRS at 2 weeks after ECMO are associated with survival at 18 months after ECMO with a score ?85 on VABS-III; (3) Determine whether metabolic and lipid neuroinflammatory pathways will distinguish between at-risk for, acute, and recovery phases of neurologic injury during ECMO.